Dataset Information

Association between neurite metrics and tau/inflammatory pathology in Alzheimer's disease.

ABSTRACT: Introduction:The molecular mechanism of neurodegeneration, including tau and neurite complexity, is an important topic in Alzheimer's disease (AD) research. Methods:We recruited 27 amyloid-positive individuals identified through 11C-Pittsburgh compound B (PiB) positron emission tomography (PET) and 31 amyloid-negative individuals with normal cognition. All participants underwent 11C-PiB and 18F-THK5351 PET and magnetic resonance imaging (MRI) with neurite orientation dispersion and density imaging (NODDI) protocol. The neurite density index (NDI), orientation dispersion index (ODI), and PET images were analyzed to calculate voxel-wise correlations among the imaging modalities and correlations with cognitions. Results:In the amyloid-positive participants, there were significant negative correlations between 18F-THK5351 and NDI and between 18F-THK5351 and ODI. The bilateral mesial and lateral temporal lobes were mainly involved. Regarding cognition, 18F-THK5351 showed more marked associations with all cognitive domains than the other modalities. Discussion:Tau and neuroinflammation in AD may reduce the neurite density and orientation dispersion, particularly in the mesial and lateral temporal lobes.

SUBMITTER: Sone D

PROVIDER: S-EPMC7656172 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Association between neurite metrics and tau/inflammatory pathology in Alzheimer's disease.

Sone Daichi D Shigemoto Yoko Y Ogawa Masayo M Maikusa Norihide N Okita Kyoji K Takano Harumasa H Kato Koichi K Sato Noriko N Matsuda Hiroshi H

Alzheimer's & dementia (Amsterdam, Netherlands) 20201111 1

<h4>Introduction</h4>The molecular mechanism of neurodegeneration, including tau and neurite complexity, is an important topic in Alzheimer's disease (AD) research.<h4>Methods</h4>We recruited 27 amyloid-positive individuals identified through <sup>11</sup>C-Pittsburgh compound B (PiB) positron emission tomography (PET) and 31 amyloid-negative individuals with normal cognition. All participants underwent <sup>11</sup>C-PiB and <sup>18</sup>F-THK5351 PET and magnetic resonance imaging (MRI) with ...[more]

PMID: 33204813

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Project description:Alzheimer's disease (AD) is defined by the presence of intraneuronal neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau aggregates as well as extracellular amyloid-beta plaques. The presence and spread of tau pathology through the brain is classified by Braak stages and thought to correlate with the progression of AD. Several in vitro and in vivo studies have examined the ability of tau pathology to move from one neuron to the next, suggesting a "prion-like" spread of tau aggregates may be an underlying cause of Braak tau staging in AD. Using the HEK293 TauRD-P301S-CFP/YFP expressing biosensor cells as a highly sensitive and specific tool to identify the presence of seed competent aggregated tau in brain lysate-i.e., tau aggregates that are capable of recruiting and misfolding monomeric tau-, we detected substantial tau seeding levels in the entorhinal cortex from human cases with only very rare NFTs, suggesting that soluble tau aggregates can exist prior to the development of overt tau pathology. We next looked at tau seeding levels in human brains of varying Braak stages along six regions of the Braak Tau Pathway. Tau seeding levels were detected not only in the brain regions impacted by pathology, but also in the subsequent non-pathology containing region along the Braak pathway. These data imply that pathogenic tau aggregates precede overt tau pathology in a manner that is consistent with transneuronal spread of tau aggregates. We then detected tau seeding in frontal white matter tracts and the optic nerve, two brain regions comprised of axons that contain little to no neuronal cell bodies, implying that tau aggregates can indeed traverse along axons. Finally, we isolated cytosolic and synaptosome fractions along the Braak Tau Pathway from brains of varying Braak stages. Phosphorylated and seed competent tau was significantly enriched in the synaptic fraction of brain regions that did not have extensive cellular tau pathology, further suggesting that aggregated tau seeds move through the human brain along synaptically connected neurons. Together, these data provide further evidence that the spread of tau aggregates through the human brain along synaptically connected networks results in the pathogenesis of human Alzheimer's disease.

Dataset Information

Association between neurite metrics and tau/inflammatory pathology in Alzheimer's disease.

Publications

Association between neurite metrics and tau/inflammatory pathology in Alzheimer's disease.

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